Immune function is regulated by the balance of activating and inhibitory signals mediated by immune cell-surface receptors (Lanier, Nature Immunol. (2001) 2:23-27; Smith et al., Immunol. Rev. (2001) 181:115-125; Moretta et al., Annu. Rev. Immunol. (2001) 19:197-223; Diefenbach & Raulet, Curr. Opin. Immunol. (2003) 15:37-44.). Among these receptors, there are families that harbor extracellular regions that have a highly conserved amino-acid sequence but have different intracellular domains responsible for activation and inhibitory signaling. Thus, activating and inhibitory members of these families can generally recognize the same or very similar ligands with slightly different specificities, presumably resulting in fine-tuning of immune regulation. Since they are involved in both the activation and inhibition of immune function, they are generally referred to as paired receptor families. Paired immunoglobulin-like (Ig-like) type 2 receptors (PILRs) are one of the paired receptor families. Inhibitory receptors possess immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in their cytoplasmic domains and deliver inhibitory signals via tyrosine phosphatases, such as SHP-1. The ITIM-bearing receptor PILR-alpha recruits SHP-1 via its amino-terminal SH2 domain and is likely to have cellular inhibitory potential. The lack of a cytoplasmic tail and the presence of the transmembrane lysine residue in the second receptor, PILR-beta, suggest its potential activating function. See Fournier et al., J. Immunol. (2000) 165:1197-1209; Mousseau et al., J. Biol. Chem. (2000) 275:4467-4474.; Shiratori et al., J. Exp. Med. (2004) 199:525-533. Although the ligand for mouse PILR-alpha and PILR-beta was identified as CD99 (Shiratori et al., J. Exp. Med. (2004) 199:525-533), to date no human ligand has been identified for human PILRs.
Herpes simplex virus type 1 (HSV-1) is a member of the alphaherpesvirus subfamily and can cause recurrent mucocutaneous lesions on the mouth, face, or genitalia and potentially meningitis or encephalitis. Membrane glycoprotein B (gB) of HSV-1 is a second ligand for PILR-alpha (Satoh et al., Cell (2008) 132:935-944). The interaction of HSV-1 gB with PILRa mediates viral entry and cell-cell fusion. Interestingly, expression of PILRa on cells enhances HSV-1 entry, whereas expression of PILRb does not (Fan and Longnecker, J. Virol. (2010) 84(17):8664-8672). This suggests HSV-1 gB is not a ligand of PILRb, and subtle amino acid differences between a and b play a role in ligand selectivity. Interestingly, binding of PILRa to HSV-1 gB also requires sialylated O-glycans (T53, T480) (Fan et al., J. Virol. (2009) 83(15):7384-7390). PILRa specifically associates with HSV-1 gB, but not with other HSV-1 glycoproteins, although some other envelope proteins are known to be O-glycosylated (Fan et al., J. Virol. (2009) 83(15):7384-7390).
Although PILR-alpha and PILR-beta are abundantly expressed on myeloid cells, very little is known about their role in host defense against extracellular bacterial infection or in immune function. Thus, elucidating the role for PILR-alpha and PILR-beta is a necessary prerequisite for the prevention/treatment of diseases/conditions associated with PILR-alpha and/or PILR-beta dysfunction. The present disclosure identifies sialidated glycans as necessary and sufficient for hPILRa binding. The present disclosure also provides a method and compositions, such as selective binding agents, to modulate the interactions of the PILR and its ligands. Specifically, described herein are novel reagents and methods based on the interaction of infective microorganisms and/or endogenous ligands for the prevention/treatment of diseases/conditions associated with PILR-alpha and/or PILR-beta activity.